At the ASH (American Society of Hematology) annual meeting in 2017 held in Atlanta, GA, I had the opportunity to interview my friend, Professor Michael Hallek from the University of Cologne, Germany who heads up much of the important CLL research done in Germany.

Dr. Hallek points out the obvious: chronic lymphocytic leukemia (CLL) almost always comes back after treatment. That is because it is a moving target, constantly evolving.

Take Away Points:

We have known for several years now that when chronic lymphocytic leukemia relapses after chemo-immunotherapy such as FCR or BR, the incidence of 17p deletion is much more common. The CLL has “evolved” presenting with a new, more aggressive clone.

We also have known for a few years now that mutations at the site where ibrutinib binds (C481) or a downstream gain of function mutations in PLɣ2 leads to resistance to ibrutinib. The cells with these mutations have a survival advantage and eventually grow to be the dominant clone, leading to relapse. Whether these are new clones caused by the therapeutic pressure of ibrutinib or a clone that was there all along but was so tiny it couldn’t be detected until it grew is still uncertain.

Hallek’s team looked at the genetic material of CLL cells in 8 patients being treated with venetoclax and found while there were mutations present before therapy, there were more during and after therapy.

Some of these mutations may contribute to venetoclax resistance.

By knowing how resistance develops, we can respond to it by using different medications or combinations of medications.

We know much about and have discussed ibrutinib resistance in some detail in the past because it is such a critical clinical concern. Here is a basic primer with Dr. Follows on the mechanism that leads to relapse.

This article talks more about clinical options after ibrutinib stops working and includes several links if you want to dig even more deeply into the subject

We know much less about venetoclax resistance and that is why this research is so important.

Dr. Furman discussed MCL1 upregulation and new drugs to block that here as a possible way to help those who relapse on venetoclax.

Dr. Hallek’s findings, as with everything else in CLL, suggests that the reasons for resistance are far more complicated, but the good news is that research moving fast.

CLL is a moving target and often genomic unstable. It is hard to wipe out with a single drug, no matter how good it is. This makes for a strong argument for combination therapies of fixed duration to lower the risk of resistance developing.